How a New, Highly Virulent HIV Strain Was Discovered in the Netherlands
Owing to the COVID-19 pandemic, researchers, clinicians and epidemiologists are more alert than ever to the danger that the potential adverse effects of a viral variant can pose to public health.
Beyond SARS-CoV-2, a myriad of viral pathogens can infect humans and impose a significant public health and economic burden. The human immunodeficiency virus (HIV) is a key example. Classified as a “global epidemic” by the World Health Organization, it has claimed ~36.3 million lives thus far.
The epidemic has been ongoing for over 30 years. While a cure has not yet been discovered, we do have increased knowledge on how the virus is transmitted, can lead to acquired immunodeficiency syndrome (AIDS) and how best to manage symptoms and disease progression pharmacologically.
Great efforts have also been placed in monitoring the evolution of HIV to ensure that any mutations with the potential to impact the behavior of the virus are detected.
The collaborative BEEHIVE project – which stands for “bridging the epidemiology and evolution of HIV in Europe and Uganda” – is one example of such efforts. The project involves scientists from a range of institutes, including the University of Oxford. It analyzes HIV genetic data coupled with clinical patient data.
The variant, known as the “VB variant”, causes CD4 cell decline to occur twice as fast in infected individuals compared with other viral variants. This is a clinical hallmark, or “signature” of the extent of damage caused by the HIV virus. In addition, those infected with the VB variant also demonstrated an increased risk of transmitting the virus to others, the data suggests.
To understand the potential impact of the variant and the utility of the research data for informing public health decisions, policies and campaigns, Technology Networks interviewed Dr. Chris Wymant. Wymant is the lead author of the study and a senior researcher in pathogen dynamics at the BDI.
Molly Campbell (MC): For our readers that may be unfamiliar, can you discuss the current landscape of HIV strains and how this has changed over the years since the disease was first discovered?
Chris Wymant (CW): HIV mutates so quickly that every individual has a virus that is different from everyone else’s, and indeed their virus changes over time. Most of these mutations make no difference. These different viruses can be grouped, in much of the same way that a brother and sister have different DNA, but it is very similar and we can group them into the same family. At a higher level, we could group them into the same ethnicity.
The highest-level grouping for HIV is into “subtypes”, and these are strongly correlated with geography. For example, in Africa, subtypes A, C and D are most common. In Europe and the US, subtype B is most common. These differences between regions were established when HIV first began spreading around the world in earnest in the mid-twentieth century, and have changed little since.
MC: What are the current treatment options for individuals with HIV, and how could this be impacted by emerging variants?
CW: Combination antiretroviral treatment for HIV, often called ART or simply treatment, is usually highly effective. For an individual on successful treatment, the deterioration of the immune system towards AIDS is stopped, and transmission of their virus to other individuals is stopped.
Current treatments are typically in the form of a single pill taken daily – a simplification of the first treatment “cocktails” to be used against HIV. Other formulations are being developed such as injections that last a long time. These could be helpful for people in infrequent contact with the health system, such as in remote rural communities in sub-Saharan Africa.
Just as there is an arms race between the HIV virus and the immune system within any given individual – each continually trying to beat the other – at a higher level, medical researchers strive to develop new treatments that combat HIV. But HIV is evolving and may begin to change to escape from the effects of treatment. Many countries affected by HIV perform monitoring for signs of such drug-resistance evolution. The worst-case scenario would be the emergence of a variant that combines high virulence, high transmissibility and resistance to treatment. The variant we discovered [in the new study] has only the first two of these properties.
MC: Can you talk about how this research study came to be as a result of the BEEHIVE project?
CW: HIV affects individuals in a remarkably variable way: some progress to AIDS within months, while others do not progress after decades. Some have viral loads (levels of virus) thousands of times higher than others. Research by our team and others before the BEEHIVE project established that this variability is partly due to the virus and not only due to people’s immune systems varying in their ability to fight the virus.
The BEEHIVE project, which began in 2014, was created to understand how changes in the virus – encoded in its genetics – cause differences in disease. The project brings together data from seven national HIV cohorts in Europe plus one in Uganda.
For many years previously, people examined only particular parts of HIV’s genetic sequence, specifically the part where drug resistance mutations are to be found. For BEEHIVE we wanted to examine the full genetic sequence of the virus, and to do this for many viruses. This was a new problem, and we needed to spend a few years developing new computational methods to make sense of this kind of data.
Fortunately, these new methods have accelerated our other projects, such as the PANGEA project that is funded specifically to use African viral sequences to better understand the policy approaches that will be most effective in preventing HIV transmission.
Pursuing the BEEHIVE project’s primary aim, we identified a large number of mutations that were correlated with a substantially higher viral load. These mutations were also correlated with each other: individuals tended to have a virus with all of these mutations, or none of them.
This collection of mutations defines a particular type of virus, what we later came to call the VB variant (because it is virulent and part of the subtype B group of viruses). Technically, we performed a “principal components analysis”: we found one direction in the space of all possible mutations that was correlated with viral load. Fifteen of the 17 individuals we found were from the Netherlands. To make sure this finding was not just a statistical fluke, we worked with colleagues at Stichting HIV Monitoring to obtain much more data from the Netherlands. We found another 92 individuals with the variant. Again, they had a substantially higher viral load than individuals with other HIV viruses, and we also found that their CD4 cells declined twice as fast. HIV attacks CD4 cells, gradually impairing an individual’s immune system, and the rate of this decline measures how much damage the virus is causing.
MC: Can you talk about how you identified the VB variant as being increasingly transmissible?
CW: We estimated transmissibility using phylogenetic methods. These methods involve constructing trees – very similar to family trees for humans – that show how closely related different individuals, viruses, organisms etc., are to each other.
One such tree represents our best guess at the evolutionary history behind an observed set of organisms – like inferring things about grandparents based only on seeing the grandchildren. A phylogenetic tree for the viruses in our dataset showed that the individuals with the VB variant had viruses that were unusually closely related to each other, i.e., there was little evolution happening between individuals acquiring the virus and passing it on. That’s a signal that the virus is moving from person to person quickly.
MC: You estimate that the variant first arose during the late 1980s and 90s in the Netherlands, spread more quickly than other variants in the 2000s and then declined in spread around 2010. Can you talk more about how you have reached these estimations?
CW: Reconstructing the evolutionary history behind the viruses we did see allows us to infer things about past viruses we didn’t see. Regarding the declining spread since around 2010, we also looked at the simpler metric of numbers of individuals diagnosed with this variant each year.
MC: Are there any limitations to this piece of work that you wish to highlight?
CW: We described many different properties of this new variant. However, we didn’t explain the mechanism through which it has higher virulence.
Our research group – Pathogen Dynamics, in the Big Data Institute, Nuffield Department of Medicine, University of Oxford, led by Professor Christophe Fraser – has a wide range of expertise in the evolutionary epidemiology of viruses. We do the experiments to determine the genetic sequences of viruses, the bioinformatics to make sense of that data, the phylogenetics to understand evolution and mathematical modeling to bring it all together, with the aim of answering certain questions of interest, such as health intervention effectiveness.
We do not have expertise in cellular biology, and so we present this finding to pass the baton to people who can study the interaction of this virus with immune system cells in controlled experimental conditions.
Also, as explained above, our conclusion regarding increased transmissibility was arrived at more indirectly than our conclusions regarding higher viral load and CD4 decline, which could be obtained using relatively simple statistics. This is an almost universal caveat to such studies. Though we can count viral particles and CD4 cells in the blood, we usually cannot count how many times each person transmitted the virus because we don’t know who passed on the virus to whom. To say anything about transmission generally requires making a set of assumptions about how the viral genetic sequences relate to what we want to know, through an evolutionary history.
MC: How can the results of this study be utilized?
CW: We hope that experimental study of how this variant attacks the immune system cells, and how this differs from normal, could tell us something we do not know that applies to HIV generally and not just this variant. Better understanding of this process could lead to new ways to stop it or slow it down, i.e., to new treatments.
The VB variant of HIV provides a concrete example for the study of virulence evolution for viruses generally, which has been widely studied through theoretical means with few real-world examples to consider.
We found that on average, individuals with this variant would be expected to progress from diagnosis to “advanced HIV” in nine months, if they do not start treatment and are diagnosed in their thirties (the progression is faster still if they are older).
Advanced HIV is known to cause long-term health problems. This finding therefore serves as an important reminder of World Health Guidelines on testing and treatment; testing should be regular for those at risk of acquiring the virus, and treatment should be started immediately when someone is diagnosed.
Dr. Chris Wymant was speaking to Molly Campbell, Senior Science Writer for Technology Networks.
Reference: Wymant C, Bezemer D, Blanquart F et al. A highly virulent variant of HIV-1 circulating in the Netherlands. Science. 2022. doi: 10.1126/science.abk1688.